The presence of donor-specific alloantibodies (DSA) is now an accepted phenomenon in waitlisted kidney recipients (1, 2).
It is now clear that the presence of pre- or posttransplant DSA is a major determinant of allograft injury (1, 3–5). Patients with pretransplant DSA have an increased risk of antibody- mediated rejection (AMR) associated with a pejorative short- and long-term graft outcome (1, 3, 6). Importantly, even in the absence of frank AMR, graft survival of patients with positive DSA remains lower than in those without DSA (1).
These observations have led to the progressive expansion of our notions of what constitutes antibody-mediated allograft injury from hyperacute rejection in the early days to AMR and now to subclinical and chronic AMR (1, 2, 7–10). It has been demonstrated that these latter two emerging immunohistopathologic entities are associated with the presence of DSA and have a pejorative effect on graft survival (1, 9), becoming a significant problem for all transplant centers dealing with patients at high immunologic risk, even those performing desensitization protocols.
Given the growing number of sensitized patient in the waiting list, numerous strategies have been developed ranging from the exclusion of these patients from transplantation to desensitization protocols (11–13) and prophylactic treatment intensification (14). In this setting, the immunomodulatory properties of intravenous immunoglobulin (IVIg) have encouraged its use for posttransplant prophylactic purposes in patients with DSA (3, 15). More recently, we demonstrated that high dose IVIg initiated posttransplant in kidney recipients with preformed DSA was associated with adequate short term graft survival, but patients nonetheless showed a high prevalence of IFTA and transplant glomerulopathy lesions at 1 year post transplant. These results increased the possibility that a more intensive prophylactic immunosuppressive strategy started at day 0 might be more effective in this high-risk selected population.
Rituximab, a chimeric anti-CD20 monoclonal antibody, has proven to be effective as a desensitizing agent (13) and in the treatment of AMR (16). In addition, plasmaphereses are now part of desensitization strategies (13) and are used in the treatment of clinical AMR (16).
The principal objective of this study was to determine the clinical, immunologic, functional, and histologic course of patients with preformed DSA receiving a deceased-donor kidney transplant, according to two prophylactic strategies all started at day 0: (i) using posttransplant high-dose IVIg and (ii) a more intensive approach consisting in posttransplant IVIg/anti-CD20/PP.
From January 2002 to March 2007, 806 kidney transplantations were performed at our institution, of which 54 (6.7%) were in patients who preformed DSA. These patients were transplanted with a single ABO-compatible kidney transplant all from a deceased donor. Two different therapeutic strategies were used, each beginning at day 0 of transplantation. From January 2002 to December 2005, one strategy was used. Subsequently, a second more intensive strategy was used for all succeeding patients (see below).
Definition of the High Immunologic Risk Population
All patients included in this study had anti-human leukocyte antigen (HLA) donor-specific antibodies identified by HLA-specific single-antigen analysis in a serum taken before transplantation. Pretransplant crossmatches (CXMs) were only performed by complement-dependent cytotoxicity (CDC) according to the French regulations guidelines. For all kidney transplant recipients, negative current T-cell and B-cell CDC-CXMs were required. CXMs positive only for IgM did not prevent transplantation. A current B-cell positive CXM in patients whose current serum was positive for anti-HLA class II antibodies was considered a contraindication to transplantation.
Antibody Detection, Specificity Analysis, and Crossmatch Techniques
All immunologic analyses were performed in a single laboratory (Hôpital Saint-Louis, Paris, France). HLA typing of transplant recipients was performed by molecular biology (Innolipa HLA typing kit; Innogenetics, Belgium). For all kidney transplant donors, HLA-A, -B, -DR, and -DQ tissue typing was performed using the microlymphocytotoxicity technique with One-Lambda, Inc., Canoga Park, CA, tissue-typing trays. Blanks and difficult typings were analyzed by molecular biology.
For all patients, CXM were performed by CDC on separated B-lymphocytes or spleen cells, according to National Institutes of Health recommendations, the CDC-CXM being performed on peak and current sera. Pretransplant sera were screened in all patients by HLA-specific ELISA assays for DSA. In patients with positive DSA screening, specificities for anti-HLA class I antibodies were assessed using a high-definition single-antigen ELISA (LAT-1HD; One-Lambda, Inc.). For anti-HLA class II antibodies, we performed an ELISA (LAT 2–40; One-Lambda, Inc.) test, identifying DR and DQ subtypes on a panel of purified HLA antigens.
In addition to the ELISA method, all available pretransplant sera (peak, day 0) and posttransplant sera (3 month and 1 year after transplantation) were retrospectively tested for the presence of DSA by Luminex SA (using the same kits to get rid of the interlot and interbead variability ). Briefly, identification of class I DSA by Luminex SA (Luminex LABScreen Single Antigen; One-Lambda, Inc.) used a set of 96 beads, each one coated with a different HLA class I glycoprotein. Identification of DSA class II antibodies by Luminex SA was performed identically using a set of 76 beads coated with HLA class II antigens. Presence of antibodies was detected using a goat anti-human IgG coupled with phycoerythrin. The fluorescence of each bead was detected by a reader (LABscanTM) and recorded as the mean intensity of fluorescence (MFI). All beads showing a normalized MFI more than 300 were considered positive. For each patient, we recorded the MFI of all class I and II detected DSA, as well as the maximum MFI value (MFImax).
Induction and Maintenance Immunosuppression
Group 1 patients (n=36) received four high-dose IVIg (Endobuline, Baxter) courses (2 g/kg administered over a 96-hr period of time). The first IVIg course was started before reperfusion, with subsequent courses being given on days 21, 42, and 63 after kidney transplantation.
Group 2 patients (n=18) received the same dose of IVIg, with additional anti-CD20 rituximab together with plasmapheresis (PP). Anti-CD20 administration was conducted at day 4 at a dose of 375 mg/m2 and repeated depending on CD19+ cell count. PP was performed immediately after transplantation at a rate of 3 per week during 3 weeks (Table 1).
Patients from both groups received a sequential quadritherapy consisting of (i) induction treatment (10-day course of rabbit rabbit antithymocyte globulin (ATG), Thymoglobulin; Genzyme, Lyon, France, at a dose of 75 mg/day, or intravenous basiliximab, Simulect; Novartis Pharma AG, Basel, 20 mg at days 0 and 4, (ii) calcineurin inhibitor (Cyclosporine, Neoral, Novartis or tacrolimus Prograf, Astellas), (iii) mycophenolate mofetil (CellCept; Roche Pharmaceuticals, Basel), 2 g preoperatively, followed by 1 g b.i.d, and (iiii) prednisone (500 mg preoperatively, 125 mg on day 1, then 20 mg/day for 15 days, progressively tapered to 10 mg/day at day 30 and continued until month 12).
Patients from both groups received the same protocol for the treatment of acute AMR episodes including steroids/IVIG/PP/anti-CD 20 (16).
All cytomegalovirus positive recipients and CMV-negative recipients of a kidney from a CMV-positive donor were given prophylaxis with valacyclovir for the first 4 months posttransplant. All patients received prophylaxis against Pneumocystiscarinii with Bactrim. All patients had blood polymerase chain reaction for BK-virus at 3 months and 1 year posttransplantation and every year thereafter.
Posttransplant Histology and Immunochemistry
All patients underwent screening graft biopsies at 3 months and 1 year posttransplant. Renal biopsies were fixed in alcohol/formaldehyde/acetic acid solution and stained with standard methods for routine microscopy. All biopsies were retrospectively reviewed by two renal pathologists (D.N. and G.H.) and a nephrologist (A.L.) blinded to clinical information. Histologic changes were graded according to the Banff '97 classification (18). Immunohistochemical C4d staining was performed in all patients on paraffin sections using human polyclonal antibody (Biomedica) and graded according to the Banff criteria (19). Diagnosis of AMR was based on the Banff criteria classification (18). Subclinical and chronic AMR were defined according to the criteria described by Haas et al. (7) and Colvin, respectively (1).
Results were expressed as numerical values and percentages for categorical variables and as mean±SD for continuous variables, with the exception of MFIs in which mean±SEM was used. Comparisons were based on the χ2 test for categorical data and the Student's t test for normally distributed continuous data. For non-Gaussian distributed parameters, we used the nonparametric Mann-Whitney U test to compare continuous variables, and the Wilcoxon test to compare two paired groups. Probability values less than 0.05 were regarded as statistically significant.
Baseline and Serological Characteristics of Our Population
From January 2002 to March 2007, among the 806 kidney transplantations performed at our institution, 54 (6.7%) were in patients who preformed DSA, all receiving an ABO-compatible deceased-donor kidney transplant. Two different strategies were used sequentially at day 0: group 1 (n=36) received a quadritherapy and high-dose IVIgs. Group 2 (n=18) additionally received PP/anti-CD 20 immediately after transplantation (Fig. 1).
Groups 1 and 2 were similar with regards to recipient age, donor age, and cold ischemia time.
Peak and day 0 class II DSA MFI was similar in both groups. However, group 2 (IVIg/anti-CD20/PP) had a higher class I DSA MFI in peak and day 0 sera compared with group 1. The peak values for class I or II MFImax DSA were similar in both groups (8747±779 vs. 8837±1198 in group 1 and 2, respectively, P=NS). Finally, at day 0, class I or II MFImax DSA was 5425±807 and 5150±1477 in groups 1 and 2, respectively (P=NS). The mean time between peak and day 0 serum was 5.6±3.9 years. There was natural attrition of the DSA MFI from peak serum to day 0 serum (see Fig. 2A). However, the behavior of the DSA pretransplant from peak to day 0 (decreasing vs. stable or increasing) did not affect posttransplant immunologic, functional, and morphologic parameters.
Among the 27 and 14 patients with available serum at day 0 in groups 1 and 2, respectively, 16 (59.2%) and seven patients (50%) had anticlass II DSA (P=NS).
The baseline patients characteristics are presented in Table 2 and Figure 2A.
Clinical and Functional Outcome
During a mean follow-up of 35.4±17 months and 19.5±9.3 months in groups 1 and 2, respectively (because of the sequential nature of the study), a total of 10 acute AMR occurred: seven in group 1 (19.4%) and three in group 2 (16.6%, P=NS). In group 1, the AMR episodes occurred at days 8, 38, 58, 60, 108, 235, and 1055 posttransplantation, whereas in group 2, AMR occurred at days 8, 61, and 183 posttransplantation.
The 3-month measured glomerular filtration rate (mGFR) was 47.5±15.7 and 63.9±15.8 mL/min/1.73 m2 in groups 1 and 2, respectively (P<0.001). The 1-year mGFR was 43.1±16.2 and 53.8±15.6 mL/min/1.73 m2 in groups 1 and 2, respectively (P=0.04). The proteinuria at 1 year was also higher in group 1 compared with group 2 (0.30±0.34 g/L and 0.10±0.08 g/L, respectively, P=0.05).
At last follow-up, six patients lost their grafts (four in group 1 and two in group 2, P=NS) due to chronic rejection occurring at 3 and 4 years after transplantation (n=3 in group 1 and n=1 in group 2), artery thrombosis (n=1, group 1), and autoimmune nephropathy recurrence (n=1, group 2). Two patients died during follow-up (1 in each group): one patient due to sepsis (group 1) and one patient due to cerebral bleeding after graft loss (group 2).
Three-month and 1-year screening biopsies results analyzed according to treatment are detailed in Table 3. At 3 months, there was a trend to higher C4d score and to higher rate of transplant glomerulopathy in group 1 compared with group 2. At 1 year, group 1 patients showed a significantly higher peritubular capillary score (1.6±0.2 vs. 1±0.2, P=0.01) and a higher rate of transplant glomerulopathy (38% vs. 7%, respectively, P=0.03). There was a trend for higher IF/TA scores in group 1 compared with group 2 (P=0.09). Noteworthy, subclinical AMR was much more frequent in group 1 than in group 2 at both 3 months (43.3% vs. 6.6%, P=0.04) and 12 months (44.8% vs. 7.1%, P=0.02). In the same way, chronic AMR lesions at 1 year were overrepresented among group 1 patients as compared with group 2 (41.3% vs. 13.3%, respectively, P=0.03).
Evolution of Posttransplant DSA According to Prophylactic Treatment
The posttransplant course of DSA MFI is presented in Table 4.
At 3 months, the class II MFImax DSA was significantly higher in group 1 (2269±569) as compared with group 2 (354±315, P=0.02). At 1 year, class II MFImax DSA remained higher in group 1 than in group 2 (2918±533 vs. 299±168, P=0.06). The decline in MFImax from day 0 to 1 year was 44%±13% in group 1, compared with 80%±8% in group 2 (P=0.02; Fig. 2B). Finally, at 1 year, 75% of group 1 vs. 28.5% of group 2 patients remained DSA positive (P<0.01).
Adverse Events and Complications
During the mean follow-up of 31±16 months, 32 severe infectious complications occurred in 29 patients (54%). Of note, there was no difference between the two groups. Eight patients experienced viral complications including three cases of CMV, three cases of BK virus nephropathy, and two cases with BK viremia without related nephropathy. Twenty-four bacterial complications occurred: 13 pyelonephritis, seven pneumonitis in addition to one tuberculosis, one P. carinii infection, two bacterial colitis, and two wound infections. Among these infectious complications, six cases of septic shock (11%) were observed: three within the first 6 months posttransplantation, one case at 2 years posttransplantation, and two cases thereafter. Among the six cases of septic shock, four occurred in patients who had been previously treated for clinical AMR. One cervical cancer was observed which was surgically treated. No case of posttransplant lymphoproliferative disorder was observed during follow-up. Neither renal dysfunction nor acute renal failure related to IVIg infusion was reported.
The most important result of this study is that the group of patients receiving the more intensive posttransplant prophylactic regimen (i.e., PP/IVIg/anti-CD20 group), despite similar rates of early acute humoral rejection, demonstrated significant differences in long-term function and histology compared with patients receiving IVIg alone. These differences were characterized by a significant decrease in DSA and a decrease in chronic AMR rate at 1 year.
Advancements in the field of immunosuppressive regimens together with improvement of immunologic techniques have enabled patients previously considered as poor or unreasonable candidates for transplantation to receive successful transplants (11, 12, 20–23). Given the growing number of sensitized patients on the waiting list, numerous strategies have been developed ranging from the exclusion of these patients from transplantation to desensitization protocols and prophylactic treatment intensification (11–14).
Desensitization protocols have proved their efficiency in reducing time on the waiting list, but seem to be more suited to living donation and less appropriate or feasible for recipients of a deceased-donor kidney transplant. Consequently, certain patients undergoing desensitization programs do not have complete removal of all DSAs but rather a reduced antibody activity pretransplant. To date, there has been no consensus as to the strategy to adopt in patients who have a persistent immunologic risk at day 0.
Since 2002, our group has been performing kidney transplantations in individuals with preformed DSA receiving ABO-compatible deceased donors (15). Our initial protocol used the association of quadritherapy together with high-dose IVIg started at day 0 of transplantation. Our preliminary experience using this protocol showed acceptable short-term graft outcome, but was unfortunately associated with a high rate of transplant glomerulopathy and IF/TA lesions in 1 year screening biopsies. Because of these worrisome results, we subsequently developed a more intensive approach from January 2006 onward, adding to the above protocol anti-CD20 together with PP started in the days after transplantation.
In this study, we found that patients having the more intensive prophylactic therapy showed significantly lower scores for peritubular capillary margination, transplant glomerulopathy, and IF/TA at 1 year, and other values showed similar trends. As an example, the rate of transplant glomerulopathy at 1 year was 7% in the PP/rituximab group compared with 38% in the no PP/rituximab group (P=0.03). Noteworthy is the lower incidence of chronic AMR observed in the IVIg/rituximab/PP group as compared with the IVIg group (13.3% vs. 41.3%, respectively, P=0.03).
Immunologically, there were marked differences in DSA MFImax levels between the two groups particularly for class II, both at 3 months and 1 year. At both intervals, group 2 showed significantly lower levels of positivity for DSA class I or II. Titers for both class I and II DSA declined in both groups posttransplant (Table 4), but much more impressively in group 2 in which the decline in DSA MFImax was 80% compared with 44% in group 1 (P<0.05). Interestingly, there were also marked differences in the behavior of the two DSA classes (Table 4): class I did not vary significantly between the two treatment groups at 3 months or 1 year. In contrast, class II values were strikingly lower at both time intervals and mirrored the differences in histologic lesions (5, 24, 25).
It is now clear that the presence of posttransplant DSA is a major determinant of AMR (1, 3). Recently, the spectrum of antibody-mediated allograft injury has been extended to subclinical and chronic-AMR that are becoming a significant problem for all transplant centers dealing with patients at high immunologic risk, even those performing desensitization protocols (1, 2, 7–10, 26).
Of note, in this study, although the intensive prophylactic strategy did not have any effect on the occurrence of overt acute AMR, group 2 patients exhibited a significant decrease in microcirculation inflammation lesions and chronic AMR in 1-year protocol biopsies.
In terms of renal function, there was significant difference in GFR between the two groups at 1 year, approximately 11 mL/min/1.73 m2 greater in group 2 than in group 1 (Table 2). It seems likely that this is at least in part the consequence of greater transplant glomerulopathy and chronic AMR in group 1, both of which have been recognized as detrimental to graft function (10, 27, 28). Similarly, the significantly greater proteinuria in group 1 at 1 year (P=0.05) seems likely to be the clinical reflection of transplant glomerulopathy, over-represented in this group.
Several hypotheses can be put forward regarding the reason that the prophylactic strategy we adopted for group 2 was associated with lowering of antibody titers: First, anti-CD20 antibodies have the ability to decrease B cells that express CD20 and make anti-HLA antibodies (29, 30), making this molecule theoretically beneficial in desensitization and treatment of AMR (31). In both these conditions, reduction or elimination of DSA has been shown (22, 32). However, anti-CD20 has no effect on plasma cells that are the primary source of antibody production and has no immediate effect on circulating antibody levels, such that rituximab used alone might be of limited benefit.
The rationale of combining rituximab with IVIg would be through their possible synergistic effects already demonstrated in autoimmune skin diseases (33), a notion also supported by the recent data obtained by Vo et al. in the field of desensitization (13). According to our study, it seems likely that the effect of rituximab on B lymphocytes depletion may be prolonged. Indeed, levels of CD19 circulating cells reached a mean of 6 cells/mm3 at 1 year posttransplantation in the PP/rituximab group versus 135 cells/mm3 before transplantation (data not shown). Finally, PP has a potential benefit by the way of DSA clearance (23) and has been used successfully in combination with anti-CD20 in the field of desensitization (13) and in the treatment of AMR (16). Nevertheless, studies comparing IVIg/anti-CD20 with or without PP are lacking so that the benefit of PP alone cannot be evaluated at the present time.
In this study, we cannot discriminate the respective benefit of each drug (i.e., IVIg, anti CD-20, and PP). Nevertheless, group 1 results clearly suggest the relatively poor performance of posttransplant IVIg alone in preventing chronic glomerular endothelial damage induced by HLA antibodies (15). Therefore, it seems likely that IVIg may have acted synergistically with rituximab. Recently, Fehr et al. (34) reported in four kidney recipients with chronic AMR that rituximab/IVIG reduced donor-specific antibodies titers in 50% of patients with improved graft function in all patients treated by this protocol.
Finally, It seems reasonable to speculate that the success of this strategy relates to the combined effects of treatments acting on different targets by different mechanisms.
In this study, basiliximab was more frequently used in group 1 patients when compared with group 2 patients. The allocation of basiliximab/thymoglobuline was sequential, justified by the results published with ATG for patients at high immunologic risk (35). Consequently, we cannot formally exclude that this may have partly contributed to the differences observed in both groups. However, we failed to find any differences in acute AMR rate, 1-year graft function, histologic changes, and class I/II DSA MFI between basiliximab- and ATG-treated patients. Therefore, it is unlikely that this alone could have accounted for the differences we have found between groups.
Finally, the aim of this study was not to attribute all the differences between groups to the anti-CD20/PP protocol per se, but rather to demonstrate that in this high-risk population a more intensive prophylactic immunosuppressive strategy started at day 0 might be more effective in preventing antibody-mediated graft lesions.
Several limitations must be acknowledged in our study including its small sample size, its retrospective design, and the different follow-up observed between the two groups. Consequently, late graft losses may not have been picked up in group 2, thus representing a potential bias in the outcome analysis. Consequently, we focused on the 1-year data, which are available for all patients in both groups and used GFR and histologic lesions at 1 year as a proxy for graft survival.
Given the important dilemma of transplanting sensitized patients awaiting deceased donor kidney transplant and the prophylactic strategy to adopt at day 0, the results of this study increases the possibility that a more intensive prophylactic immunosuppressive strategy started at day 0, including IVIg/anti-CD20/PP in this high-risk selected population might be more effective in preventing acute and chronic antibody-mediated graft lesions. Despite the fact that, in this study, we were unable to detect differences in the prevalence of clinical acute AMR, we nonetheless have found that the more intensive protocol was associated with a lower rate of microcirculation inflammation lesions and chronic AMR at 1 year. Future prospective randomized studies are needed to assess the best strategies to be applied in light of the pretransplant immunologic risk stratification. A longer follow-up is also needed to assess long-term outcome, and the prevalence of infectious complications in patients receiving active T- and B-cell depleting therapies.
The authors thank Sophie Lechaton who left recently.
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